Serotonin 5-HT, receptor partial activator

ABSTRACT

This invention provides a serotonin 5-HT 3  receptor partial activator which has a serotonin 5-HT 3  receptor activating action, in addition to its serotonin 5-HT 3  receptor antagonism, and does not cause constipation as a side effect.  
     Particularly, based on the finding that newly synthesized benzoxazole derivatives typified by the compounds of the following formula (2) have strong serotonin 5-HT 3  receptor antagonism and serotonin 5-HT 3  receptor activating action, this invention provides these benzoxazole derivatives as serotonin 5-HT 3  receptor partial activators.  
                 
 
     In the above formula, R 1  to R 4  may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R 1  and R 2  may be linked together to form a ring structure, namely benzene ring; R 5  represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; and m is an integer of 1 to 4.

FIELD OF THE INVENTION

[0001] This invention relates to novel and known benzoxazolederivatives, more particularly to a serotonin-5-HT₃ receptor antagonistor a serotonin 5-HT₃ receptor partial activator, which has beendeveloped on the basis of the effective and selective action of saidderivatives upon serotonin 5-HT₃ receptors that are distributed insmooth muscles such as of digestive organs and the like and in centralnervous system, intestinal nervous system and the like.

BACKGROUND OF THE INVENTION

[0002] It has been revealed that serotonin 5-HT₃ receptor antagonistscan inhibit nausea and emesis as side effects caused by the use ofcisplatin and the like carcinostatic agents and by radiation treatments,and several compounds thereof are now used in the clinical field. Inaddition to this, development on their use as digestive organ functioncontrolling drugs has recently been examined.

[0003] The inventors of the present invention have already found thatcertain benzoxazole derivatives are possessed of serotonin 5-HT₃receptor antagonism (JP-A-6-345744; the term “JP-A” as used herein meansan “unexamined published Japanese patent application”).

[0004] When a compound having only serotonin 5-HT₃ receptor antagonismis administered as a digestive organ function controlling drug, it caninhibit diarrhea but poses a problem of frequently causing constipationas a side effect.

SUMMARY OF THE INVENTION

[0005] In view of the above, it therefore becomes an object of thepresent invention to provide a serotonin 5-HT₃ receptor partialactivator which is possessed of not only serotonin 5-HT₃ receptorantagonism but also serotonin 5-HT₃ receptor activating action and isuseful in getting rid of constipation side effect.

[0006] Using an evaluation test system in which serotonin 5-HT3 receptorantagonizing and activating actions are judged by a guinea pig excisedileum contraction action which can be used as an index of the serotonin5-HT₃ receptor activating action upon digestive organs, the inventors ofthe present invention have found that certain compounds among thebenzoxazole derivatives disclosed in JP-A-345744 are possessed ofserotonin 5-HT3 receptor partial activity. As a result of subsequentsynthesis and evaluation studies, it was found that certain novel orknown benzoxazole derivatives are possessed of not only serotonin 5-HT₃receptor antagonism but also serotonin 5-HT₃ receptor activating actionand are useful as strong serotonin 5-HT₃ receptor partial activators.The present invention has been accomplished on the basis of thesefindings.

[0007] Accordingly, the gist of the present invention resides in thecompounds of the following formulae (1) to (3):

[0008] wherein R₁ to R₄ may be the same or different from one anotherand each represents a hydrogen atom, a halogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group or a substituted or unsubstituted amino group, or optionaltwo groups of R₁ to R₄ may be linked together to form a ring structurewhich is a 5- or 6-membered ring composed of carbon atoms alone orcarbon atoms and 1 to 2 hetero atoms, selected from a cyclohexane ring,a benzene ring, a pyridine ring, a piperidine ring and a pyrrolidinering; and Y represents a saturated or unsaturated, substituted orunsubstituted 4- to 8-membered hetero ring containing 1 to 3 nitrogenatoms as the ring constituting atoms and carbon atoms as the remainingatoms, which is selected from the group consisting of an azetidine ring,a pyrrolidine ring, a piperidine ring, a pyridine ring, an imidazolering, a pyrazinyl ring, a pyridazinyl ring, a triazole ring, ahomopiperidine ring, a 1,4-diazacyclooctanyl ring and a1,5-diazacyclooctanyl ring;

[0009] wherein R₁ to R₄ may be the same or different from one anotherand each represents a hydrogen atom, a halogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group or a substituted or unsubstituted amino group, or twogroups of R₁ and R₂ may be linked together to form a ring structure,namely a benzene ring, with the proviso that compounds in which all ofR₁ to R₄ are hydrogen atoms are excluded; R₅ represents a hydrogen atom,a substituted or unsubstituted lower alkyl group or a substituted orunsubstituted lower alkenyl group; and m is an integer of 1 to 4; and

[0010] wherein R₁ to R₄ may be the same or different from one anotherand each represents a hydrogen atom, a halogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group or a substituted or unsubstituted amino group, or twogroups of RI and R₂ may be linked together to form a ring structure,namely a benzene ring, with the proviso that compounds in which all ofR₁ to R₄ are hydrogen atoms are excluded; R₅ and R₆ may be the same ordifferent from each other and each represents a substituted orunsubstituted lower alkyl group or a substituted or unsubstituted loweralkenyl group; m is an integer of 1 to 4; and X- represents a halogenion.

[0011] Further, the second aspect of the present invention resides in aserotonin 5-HT₃ receptor partial activator containing, as an activeingredient, the compounds of any one of the formulae (1) to (3) or acompound represented by the formula (4) shown hereinafter, for example,for use in the treatment and prevention of functional disorders ofdigestive organs and diarrhea.

[0012] Other objects and advantages of the present invention will bemade apparent as the description progresses.

DETAILED DESCRIPTION OF THE INVENTION

[0013] In the aforementioned formula (1), examples of the ring structurerepresented by Y include an azetidine ring, a pyrrolidine ring, apiperidine ring, a pyridine ring, an imidazole ring, a pyrazinyl ring, apyridazinyl ring, a triazole ring, a homopiperidine ring, a1,4-diazacyclooctanyl ring and a 1,5-diazacyclooctanyl ring. Preferably,Y is 4-pyridinyl group, 4-piperidinyl group, 4-homopiperidinyl group,3-pyrrolidinyl group, 1-(1,4-diazacyclooctanyl) group or1-(1,5-diazacyclooctanyl) group.

[0014] The substituent of Y is a group which is linked to a nitrogenatom of Y and selected from the group consisting of a straight orbranched C₁-C₄ alkyl group and a straight or branched C₂-C₄ alkenylgroup, and at least one hydrogen atom of the alkyl or alkenyl group maybe substituted with a substituent group which may be selected from thegroup consisting of a hydroxyl group, a halogen atoms, a carbamoylgroup, an amino group and a cyano group.

[0015] Particularly preferred compounds of the formula (2) are those inwhich R₁ to R₄ may be the same or different from one another and eachrepresents a hydrogen atom, a halogen atom or a substituted orunsubstituted lower alkyl group, or two groups of R₁ and R₂ may belinked together to form a benzene ring; R₅ is a substituted orunsubstituted lower alkyl group; and m is an integer of 2 or 3, with theproviso that compounds in which all of R₁ to R₄ are hydrogen atoms areexcluded because such compounds are disclosed in JP-A-6-345744.

[0016] Definition

[0017] According to this specification, the alkyl or alkenyl as a groupor a part of a group may be either straight chain or branched chain.Also in this specification, the term halogen atom means fluorine,chlorine, bromine or iodine atom.

[0018] Compounds of Formulae (1) to (3)

[0019] In the formulae (1) to (3), the lower alkyl group represented byany one of R₁ to R₆ is a C₁-C₄ alkyl group, and at least one hydrogenatom of the alkyl group may be substituted with a substituent groupwhich may be selected from the group consisting of a halogen atom, ahydroxyl group, a carbamoyl group, an amino group and a cyano group.

[0020] The lower alkenyl group represented by any one of RI to R₄ is aC₂-C₄ alkenyl group, and at least one hydrogen atom of the alkenyl groupmay be substituted with a substituent group which may be selected fromthe group consisting of a hydroxyl group, a halogen atoms, a carbamoylgroup, an amino group and a cyano group.

[0021] Examples of the substituent group of the amino group representedby any one of R₁ to R₄ include those which are selected from the groupconsisting of a straight or branched C₁-C₄ alkyl group, a straight orbranched C₁-C₄ alkylcarbonyl group, a straight or-branched C₂-C₄ alkenylgroup and a benzylidene group which may have a phenyl group.

[0022] Use and Pharmaceutical Composition of the Compounds of Formulae(1) to (3) and a Compound of Formula (4)

[0023] According to the present invention, the compounds of formulae (1)to (3) and a compound represented by formula (4):

[0024] (wherein m is an integer of 1 to 4) are possessed of serotonin5-HT₃ receptor antagonism and serotonin 5-HT₃ receptor activatingaction. In consequence, they are useful as drugs for the treatment andprevention of diseases in which serotonin 5-HT₃ is concerned. Examplesof the serotonin 5-HT₃-concerned diseases include emesis caused by theuse of cisplatin and the like carcinostatic agents or by radiationtreatments, as well as difficulty of gastrointestinal moving, irritablecolon syndrome, headache, neuralgia, anxiety, depression, psychosis andthe like.

[0025] In addition to the serotonin 5-HT₃ receptor antagonism, thecompounds of formulae (1) to (4) of the present invention also showserotonin 5-HT₃ receptor partial activation action having serotonin5-HT₃ receptor activating action, so that they are particularly usefulin the treatment and prevention of difficulty of gastrointestinal movingand irritable colon syndrome as a digestive organ function controllingdrug which can inhibit diarrhea without causing constipation as a sideeffect.

[0026] The compounds of formulae (1) to (4) of the present invention canbe used in the form of free bases or as pharmaceutically acceptablesalts thereof. For example, the compounds of formulae (1), (2) and (4)can be administered in the form of an appropriate acid addition salt orquaternary ammonium salt. As such salts, pharmaceutically acceptablenon-toxic salts can be exemplified. Preferred examples thereof includesalts with hydrohalogenic acids such as hydrofluoric acid, hydrochloricacid, hydrobromic acid, hydroiodic acid and the like, inorganic acidsalts such as sulfate, nitrate, phosphate, perchlorate, carbonate andthe like, salts with carboxylic acids such as acetic acid,trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lacticacid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelicacid, butyric acid, maleic acid, propionic acid, formic acid, malic acidand the like, salts with acidic amino acids such as aspartic acid,glutamic acid and the like and salts with organic acids such asmethanesulfonic acid, p-toluenesulfonic acid and the like. In addition,the compound of formula (3) is administered as a salt of a halogen anionsuch as chlorine, bromine, iodine or the like represented by X⁻ of theformula (3). Such salts of the compounds of formulae (1) to (4) show thesame level of activities of the corresponding free bases. Inconsequence, the compounds represented.by the general formulae (1) to(4), acid addition salts thereof and quaternary ammonium salts thereofare all included in the present invention.

[0027] Illustrative examples of more particularly preferred compounds ofthe present invention include, in the case of formula (1),

[0028] 2-(4-pyridyl)benzoxazole,

[0029] 2-(4-piperidyl)benzoxazole,

[0030] 2-(4-piperidyl)-5-methylbenzoxazole,

[0031] 5-chloro-2-(1-piperidyl)benzoxazole and

[0032] 5,7-dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole, in the case offormula (2),

[0033] 5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,

[0034] 5,7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole,

[0035] 6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,

[0036] 6-methylamino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,

[0037]6-benzylideneamino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,

[0038] 5-methyl-2-(1-piperazinyl)benzoxazole,

[0039] 6-amino-5-chloro-2-(1-piperazinyl)benzoxazole,

[0040] 6-dimethylamino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,

[0041] 5,7-dimethyl-2-(1-piperazinyl)benzoxazole,

[0042] 2-(4-methyl-1-piperazinyl)-5-methylbenzoxazole,

[0043] 2-(4-methyl-1-piperazinyl)-6-methylbenzoxazole,

[0044] 2-(4-methyl-1-piperazinyl)-7-methylbenzoxazole,

[0045] 2-(4-mnethyl-1-piperazinyl )-5,7-dichlorobenzoxazole,

[0046] 2-(4-methyl-1-piperazinyl )naphtho[1,2-d]oxazole

[0047] 2-(4-methyl-1-piperazinyl)-5-aminobenzoxazole,

[0048] 2-(4-methyl-1-piperazinyl)-6-amuinobenzoxazole,

[0049] 2-(4-methyl-1-piperazinyl)-5-trifluoromethylbenzoxazole,

[0050] 5-chloro-7-methyl-2-(4-mnethyl-1-piperazinyl )benzoxazole,

[0051] 5-chloro-6, 7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole,

[0052] 5,7-dichloro-6-methyl-2-(4-methyl-1-piperazinyl)benzoxazole,

[0053] 5-nmethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole,

[0054] 5,7-dimethyl-2-(4-methyl-1-homopiperazinyl) benzoxazole,

[0055] 5-chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole,

[0056] 5-chloro-7-ethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole,

[0057] 5-chloro-6-methyl-2-(4-methyl-1-homopiperazinyl ) benzoxazole

[0058] 2-(4-methyl-1-homopiperazinyl)naphtho[1,2-d]oxazole,

[0059] 5-chloro-2-(4-methyl-1-homopiperazinyl)benzoxazole,

[0060] 5-chloro-6-amino-2-(4-methyl-1-homopiperazinyl)benzoxazole,

[0061] 5,7-dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole and

[0062] 5,7-dimethyl-2-(4-methyl-1,4-diazacyclooctanyl)benzoxazole, inthe case of formula (3),

[0063] 1-allyl-1-methyl-4-(5-chlorobenzoxazol-2-yl)piperazinium iodide,

[0064] 1-allyl-1-methyl-4-(5,7-dimethylbenzoxazol-2-yl)piperaziniumiodide,

[0065] 1-allyl-1-methyl-4-(6-amino-5-chlorobenzoxazol-2-yl)piperaziniumbromide,

[0066] 1-allyl-1-methyl-4-(5-methylbenzoxazol-2-yl)piperazinium bromide,

[0067] 1-allyl-1-methyl-4-(5-trifluoromethylbenzoxazol-2-yl)piperaziniumbromide,

[0068] 1-allyl-1-methyl-4-(6-methylbenzoxazol-2-yl )piperaziniumbromide,

[0069] 1-allyl-1-methyl-4-(7-methylbenzoxazol-2-yl)piperazinium bromide,

[0070] 1-allyl-1-methyl-4-(5,7-dichlorobenzoxazol-2-yl)piperaziniumbromide and

[0071] 1-allyl-1-methyl-4-(naphtho[1,2-d]benzoxazol-2-yl)piperaziniumbromide, and in the case of formula (4),

[0072] 2-(1-piperazinyl)benzoxazole.

[0073] A pharmaceutical composition which comprises the compound of thepresent invention as its active ingredient can be administered tohuman-and animals other than human through the route of administrationof either oral or parenteral (for example, intravenous injection,intramuscular injection, subcutaneous administration, percutaneousadministration and the like).

[0074] In consequence, the pharmaceutical composition which contains thecompound of the present invention as its active ingredient is made intoappropriate dosage forms depending on the route of administration.Illustrative examples of oral dosage forms include tablets, capsules,powders, granules, syrups and the like, and those of parenteral dosageforms include intravenous, intramuscular and the like injections, rectaladministration preparations, oleaginous suppositories, aqueoussuppositories and the like. These various types of preparations can beproduced in the usual way making use of generally used fillers,disintegrators, binders, lubricants, coloring agents and the like.

[0075] Illustrative examples of non-toxic fillers which can be usedinclude lactose, glucose, corn starch, sorbitol, crystalline celluloseand the like, those of disintegrators include starch, sodium alginate,gelatin, calcium carbonate, calcium citrate, dextrin and the like, thoseof binders include dimethyl cellulose, polyvinyl alcohol, polyvinylether, methyl cellulose, ethyl cellulose, acacia, hydroxypropylcellulose, polyvinyl pyrrolidone and the like and those of lubricantsinclude talc, magnesium stearate, polyethylene glycol, hardened oil andthe like.

[0076] In the case of injections, a buffer, a pH adjusting agent, anstabilizing agent and the like may be added as occasion demands.

[0077] Amount of the drug of the present invention to be contained inthe pharmaceutical composition varies depending on the dosage form, butis generally from 0.05 to 50% by weight, preferably from 0.1 to 20% byweight, based on the total composition.

[0078] Its dose is optionally decided in each case by taking age, bodyweight, sex, difference in diseases, degree of symptoms and the like ofeach patient into consideration, but is generally from 0.5 to 1,000 mg,preferably from 1 to 300 mg, per adult per day when used as a digestiveorgan function controlling drug, and the daily dose may be administeredonce a day or by dividing it into several doses per day.

[0079] Production of the Compound of Formula (1)

[0080] The compound of formula (1) of the present invention can beproduced by various methods, but it may be produced preferably by thefollowing two typical methods in the case of a compound in which acarbon atom of Y is linked to the benzoxazole ring.

[0081] A compound represented by the formula-(6) (in the formula, R₁,R₂, R₃ and R4 are as defined in the formula (1)) is allowed to reactwith 1 to 10 equivalents of an aldehyde represented by the formula (7)(in the formula, Y is as defined in the formula (1)), thereby obtaining,among the intended compounds of formula (1) (in the formula, R₁, R₂, R₃,R₄ and Y are as defined in the foregoing), a compound in which a carbonatom of Y is linked to the benzoxazole ring.

[0082] Alternatively, a compound represented by the formula (6) (in theformula, R₁, R₂, R₃ and R₄ are as defined in the formula (1)) is allowedto react with 1 to 10 equivalents of a carboxylic acid represented bythe formula (8) (in the formula, Y is as defined in the formula (1)) toobtain the compound of formula (9) (in the formula, R₁, R₂, R₃, R₄ and Yare as defined in the formula (1)) which is then subjected tocyclization, thereby obtaining, among the intended compounds of formula(1) (in the formula, R₁, R₂, R₃, R₄ and Y are as defined in theforegoing), a compound in which a carbon atom of Y is linked to thebenzoxazole ring.

[0083] In the case of a compound in which a nitrogen atom of Y is linkedto the benzoxazole ring, it can be produced preferably by the followingmethod.

[0084] A compound represented by the formula (10) (in the formula, R₁,R₂, R₃ and R₄ are as defined in the formula (1) and Z represents ahalogen atom or a thiol group) is allowed to react with 1 to 50equivalents of a compound of nitrogen-containing ring structurerepresented by the formula (11) (in the formula, Y is as defined in theformula (1)), thereby obtaining, among the intended compounds of formula(1) (in the formula, R₁, R₂, R₃, R₄ and Y are as defined in theforegoing), a compound in which a nitrogen atom of Y is linked to-thebenzoxazole ring.

[0085] Production of the Compounds of Formulae (2) and (4)

[0086] The compound represented by the formula (2) or (4) can beproduced preferably by the following two typical methods.

[0087] A compound represented by the formula (12) (in the formula, R₁,R₂, R₃ and R₄ are as defined in the formula (2) and Z is a halogen atomor a thiol group) is allowed to react with 1 to 50 equivalents of anN-substituted alicyclic diamine represented by the formula (13) (in theformula, R₅ is a substituted or unsubstituted lower alkyl group or asubstituted or unsubstituted lower alkenyl group and m is as defined inthe formula (2)), thereby obtaining the intended compound of formula (2)(in the formula, R₁, R₂, R₃, R₄ and m are as defined in the foregoingand R₅ is a substituted or unsubstituted lower alkyl group or asubstituted or unsubstituted lower alkenyl group).

[0088] Alternatively, a compound represented by the formula (12) (in theformula, R₁, R₂, R₃ and R₄ are all hydrogen atoms or as defined in theformula (2) and Z is a halogen atom or a thiol group) is allowed toreact with an alicyclic diamine represented by the formula (14) (in theformula, m is as defined in the formula (2)) to convert into thecompound of formula (15) (in the formula, R₁, R₂, R₃ and R₄ are allhydrogen atoms or as defined in the formula (2) and m is as defined inthe formula (2)) which is a compound of the formula (2) in which R₅ ishydrogen atom or a compound of the formula (4), subsequently allowingthe resulting compound to react with 1 to 5 equivalents of a compoundrepresented by the formula (16) (in the formula, R₅ is a substituted orunsubstituted lower alkyl group or a substituted or unsubstituted loweralkenyl group and X is a halogen atom), thereby obtaining the intendedcompound of formula (2) (in the formula, R₁, R₂, R₃, R₄ and m are asdefined in the formula (2) and R₅ is a substituted or unsubstitutedlower alkyl group or a substituted or unsubstituted-lower alkenylgroup).

[0089] Production of the Compound of Formula (3)

[0090] The compound represented by the formula (3) can be producedpreferably by the following method.

[0091] That is, a compound represented by the formula (2) (in theformula, R₁, R₂, R₃, R₄ and m are as defined in the formula (2) and R₅is a substituted or unsubstituted lower alkyl group or a substituted orunsubstituted lower alkenyl group) is allowed to react with 1 to 10equivalents of a compound represented by the formula (17) (in theformula, R₆ is as defined in the formula (3) and X is a halogen atom),thereby obtaining the intended compound of formula (3) (in the formula,R₁, R₂, R₃, R₄, R₅, R₆ and m are as defined in the formula (3) and X⁻ isa halogen ion).

[0092] The reaction of compound (6) with compound (7) is quicklycompleted when they are allowed to react with each other in an organicacid such as acetic acid, trifluoroacetic acid or the like at 0 to 150°C. for 1 to 12 hours.

[0093] The compound (9) can be obtained easily when the reaction ofcompound (6) with compound (8) is carried out in a solvent such as DMFor the like at 0 to 150° C. for 1 to 12 hours in the presence of achlorination agent such as thionyl chloride or the like or a condensingagent such as DCC or the like. Also, cyclization of the compound (9) isquickly completed within 1 to 24 hours when it is allowed to undergo thereaction at 50 to 150° C. in DMF or the like solvent in the presence ofPPTS or the like acid catalyst or when it is heated at 50 to 200° C.together with polyphosphoric acid without solvent.

[0094] The reaction of compound (10) with compound (11) is quicklycompleted when they are allowed to react with each other without solventor in DMF or the like solvent in the presence of triethylamine or thelike alkylamine base at 0 to 150° C. for 1 to 12 hours.

[0095] The reaction of compound (12) with compound (13) or (14) isquickly completed when they are allowed to react with each other withoutsolvent or in DMF or the like solvent in the presence of triethylamineor the like alkylamine base at 0 to 150° C. for 1 to 12 hours.

[0096] Formation of the compound (2) or (3) by the reaction of compound(15) with compound (16) or the reaction of compound (2) with compound(17) can be effected easily when they are allowed to react with eachother in DMF or the like solvent at 0 to 150° C. for 1 to 12 hours.

[0097] The following reference examples, inventive examples and testexamples are provided to further illustrate the present invention. It isto be understood, however, that the examples are for purpose ofillustration only and are not intended as a definition of the limits ofthe invention, and therefore that various variations and modificationscan be made within the scope of the invention as a matter of course. TheNMR data in the examples are 8 values based on TMS internal standardwhen measured using 400 MHz NMR.

REFERENCE EXAMPLE 1

[0098]5-Chloro-2-mercaptobenzoxazole

[0099] A 2 g portion of 2-amino-4-chlorophenol was dissolved in 150 mlof ethanol, and the solution was mixed with 80 ml of carbon disulfideand 937 mg of potassium hydroxide and heated under reflux for 8 hours.The solvent was evaporated under a reduced pressure, and the residualoily mixture was mixed with 50 ml of 1 N hydrochloric acid aqueoussolution and extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried with magnesium sulfate and then thesolvent was evaporated under a reduced pressure. By recrystallizing thethus obtained mixture from ethyl acetate, the title compound (1.3 g) inlight yellow color was obtained.

[0100]¹H-NMR (CD₃OD) δ values: 6.97 (1H, dd), 7.14 (1H, d), 7.17 (1 H,d)

[0101] MS (EI): m/z 185 (M⁺)

INVENTIVE EXAMPLE 1

[0102] 5-Chloro-2-(4-methyl-1-piperazinyl benzoxazole

[0103] A 300 mg portion of 5-chloro-2-mercaptobenzoxazole was suspendedin 50 ml of anhydrous benzene, and the suspension was mixed with 404 mgof phosphorus pentachloride and heated under reflux for 3 hours. Thereaction solution was cooled in an ice bath and, with stirring, 1.6 g of1-methylpiperazine was added thereto. After 30 minutes of stirring, theice bath was removed to carry out 12 hours of stirring at roomtemperature, and then the reaction solution was mixed with saturatedsodium bicarbonate aqueous solution and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried withmagnesium sulfate and then the solvent was evaporated under a reducedpressure. Thereafter, the thus obtained mixture was purified by a silicagel column chromatography (ethyl acetate:methanol=20:1) to obtain thetitle compound (121 mg) in light yellow color.

[0104]¹H-NMR (CD₃OD) δ values: 2.35 (3H, s), 2.60 (4H, t), 3.70 (4H, t),7.02 (1H, dd), 7.25 (1H, d), 7.28 (1H, d)

[0105] MS (EI): m/z 251 (M⁺)

INVENTIVE EXAMPLE 2

[0106] 1-Allyl-1-methyl-4-(5-chlorobenzoxazol-2-yl piperazinium iodide

[0107] A 30 mg portion of 5-chloro-2-(4-methyl-1-piperazinyl)benzoxazolewas dissolved in 5 ml of DMF, and the solution which was stirred at roomtemperature was mixed with 100 mg of allyl iodide and then stirred for12 hours. The solvent was evaporated under a reduced pressure, and thethus obtained mixture was purified by an LH-20 gel chromatography(chloroform:methanol =1:1) to obtain the title compound (36 mg) in lightyellow color.

[0108]¹H-NMR (CD₃OD) δ values: 2.35 (3H, s), 2.60 (4H, t), 3.70 (4H, t),7.02 (1H, dd), 7.25 (1H, d), 7.28 (1H, d)

[0109] MS (FAB): m/z 292 (M⁺)

INVENTIVE EXAMPLE 3

[0110] 5,7-Dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole

[0111] Using 5,7-dimethyl-2-mercaptobenzoxazole, the title compound wasobtained in the same manner as described in Inventive Example 1.

[0112]¹H-NMR (DCl) δ values: 2.39 (6H, s), 3.03 (3H, s), 3.30 (2H, t),3.64 (2H, t), 3.75 (2H, d), 4.41 (2H, d), 6.83 (1H, s), 7.00 (1H, s)

[0113] MS (EI): m/z 245 (M⁺)

INVENTIVE EXAMPLE 4

[0114] 1-Allyl-1-methyl-4-(5,7-dimethylbenzoxazol-2-vl)piperaziniumiodide Using 5,7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole, theprocedure of Inventive Example 2 was repeated to obtain the titlecompound.

[0115]¹H-NMR (CD₃OD) δ values: 2.24 (3H, s), 2.29 (3H, s), 3.13 (3H, s),3.50-3.70 (4H, m), 3.85-3.95 (2H, m), 4.03-4.13 (2H, m), 4.12 (2H, d),5.65-5.75 (2H, m), 6.00-6.15 (1H, m), 6.68 (1H, s), 6.89 (1H, s)

[0116] MS (FAB): m/z 286 (M⁺)

INVENTIVE EXAMPLE 5

[0117] 6-Amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazble

[0118] a) Using 5-chloro-6-nitro-2-mercaptobenzoxazole, the procedure ofInventive Example 1 was repeated to obtain5-chloro-6-nitro-2-(4-methyl-1-piperazinyl)benzoxazole.

[0119]¹H-NMR (CD₃OD) δ values: 2.52 (3H, s), 2.77 (4H, t), 3.92 (4H, t),7.50 (1H, s), 8.15 (1H, s)

[0120] MS (EI): m/z 296 (M⁺)

[0121] b) A 50 mg portion of5-chloro-6-nitro-2-(4-methyl-1-piperazinyl)benzoxazole obtained in theabove step (a) was dissolved in 10 ml of methanol, and the solution wasmixed with 3 ml of 1 N hydrochloric acid aqueous solution and 10 mg ofPd/C catalyst and then, after replacing the atmosphere in the reactionvessel by hydrogen gas, stirred at room temperature for 3 hours. Thecatalyst was removed by filtration and the solvent was concentratedunder a reduced pressure. The residual oily matter was mixed withsaturated sodium bicarbonate aqueous solution and extracted with ethylacetate. The organic layer was washed with saturated brine and driedwith magnesium sulfate, and then the solvent was evaporated under areduced pressure. Thereafter, the thus obtained mixture was purified bya silica gel column chromatography (chloroform:methanol=20:1) to obtainthe title compound (38 mg) in light yellow color.

[0122]¹H-NMR (CD₃OD) 6 values: 2.30 (3H, s), 2.54 (4H, t), 3.59 (4H, t),6.82 (1H, s), 7.09 (1 H, s)

[0123] MS (EI): m/z 266 (M⁺)

INVENTIVE EXAMPLE 6

[0124] 6-Methylamino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole

[0125] A 50 mg portion of6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in5 ml of formic acid, and the solution was mixed with 3 ml offormaldehyde and stirred at room temperature for 3 hours. The solventwas concentrated under a reduced pressure, and the resulting oily matterwas mixed with saturated sodium bicarbonate aqueous solution andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried with magnesium sulfate, and then the solventwas evaporated under a reduced pressure. Thereafter, the thus obtainedmixture was purified by a silica gel column chromatography(chloroform:methanol 20:1) to obtain the title compound (28 mg) in lightyellow color.

[0126]¹H-NMR (CD₃OD) 6 values: 2.32 (3H, s), 2.55 (4H, t), 2.70 (3H, s),3.6-3.7 (4H, m), 6.85 (1H, s), 7.21 (1H, s)

[0127] MS (EI): m/z 280 (M⁺)

INVENTIVE EXAMPLE 7

[0128] 1-Allyl-1-methyl-4-(6-amino-5-chlorobenzoxazol-2-yl)piperaziniumbromide

[0129] A 50 mg portion of6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in5 ml of DMF, and the solution, while stirring at room temperature, wasmixed with 135 mg of allyl bromide and stirred for additional 2 hours.Thereafter, the solvent was evaporated under a reduced pressure and thethus obtained mixture was purified by an LH-20 gel column chromatography(chloroform:methanol =1:1) to obtain the title compound (15 mg) in lightyellow color.

[0130]¹H-NMR (CD₃OD) δ values: 3.17 (3H, s), 3.5-3.7 (4H, m), 3.8-4.2(4H, m), 4.13 (2H, d), 5.65-5.8 (2H, m), 6.0-6.15 (1H, m), 6.93 (1H, s),7.20 (1H, s)

[0131] MS (EI): m/z 306 (M⁺)

INVENTIVE EXAMPLE 8

[0132] 6-Benzylideneamino-5-chloro-2-(4-methyl-1-piperazinvl)benzoxazole

[0133] A 30 mg portion of6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in20 ml of anhydrous toluene, and the solution was mixed with 1 ml ofbenzaldehyde and heated under reflux for 6 hours. The solvent wasconcentrated under a reduced pressure, the residual oily matter wasmixed with hexane and then the thus formed precipitate was collected byfiltration to obtain the title compound (24 mg) in white color.

[0134]¹H-NMR (CD₃OD) δ values: 2.32 (3H, s), 2.58 (4H, t), 3.70 (4H, t),7.25 (1H, s), 7.30 (1H, s), 7.4-7.55 (3H, m), 7.9-8.0 (2H, m), 8.48 (1H,s)

[0135] MS (EI): m/z 354 (M⁺)

INVENTIVE EXAMPLE 9

[0136] 5-Methyl-2-(1-Piperazinyl)benzoxazole

[0137] A 100 mg portion of 5-methyl-2-mercaptobenzoxazole was suspendedin 20 ml of anhydrous toluene, and the suspension was mixed with 150 mgof phosphorus pentachloride and heated under reflux for 1 hour. Thereaction solution was cooled in an ice bath and, with stirring, 500 mgof piperazine was added thereto. After 30 minutes of stirring, the icebath was removed to carry out 1 hour of stirring at room temperature,the reaction solution was mixed with saturated sodium bicarbonateaqueous solution, and then the water layer was washed with ethyl acetateand concentrated under a reduced pressure. Thereafter, the thus obtainedmixture was purified by an LH-20 gel column chromatography(chloroform:methanol=1:1) to obtain the title compound (40 mg) in whitecolor.

[0138]¹H-NMR (DCl) δ values: 2.39 (3H, s), 3.35 (4H, t), 4.05 (4H, t),3.75 (2H, d), 7.12 (1H, d), 7.24 (1H, s), 7.39 (1H, s)

[0139] MS (EI): m/z 217 (M⁺)

INVENTIVE EXAMPLE 10

[0140] 6-Amino-5-chloro-2-(1-piperazinvl)benzoxazole

[0141] a) Using 5-chloro-6-nitro-2-mercaptobenzoxazole, the procedure ofInventive Example 9 was repeated to obtain5-chloro-6-nitro-2-(1-piperazinyl)benzoxazole.

[0142]¹H-NMR (CD₃OD) δ values: 2.91 (4H, t), 3.68 (4H, t), 7.30 (1H, s),7.98 (1H, s)

[0143] MS (EI): m/z 282 (M⁺)

[0144] b) Using 5-chloro-6-nitro-2-(1-piperazinyl)benzoxazole obtainedin the above step (a), the procedure of Inventive Example 5 was repeatedto obtain the title compound.

[0145]¹H-NMR (CD₃OD) δ values: 3.08 (4H, t), 3.63 (4H, t), 6.82 (1H, s),7.09 (1H, s)

[0146] MS (EI): m/z 252 (M⁺)

INVENTIVE EXAMPLE 11

[0147] 6-Dimethylamino-5-chloro-2-(4-methyl-1-piperazinyl benzoxazole

[0148] A 40 mg portion of6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in5 ml of methanol, and the solution was mixed with 1 ml of 1 Nhydrochloric acid aqueous solution, 1 ml of formaldehyde and 20 mg ofPd/C catalyst and then, after replacing the atmosphere in the reactioncontainer by hydrogen gas, stirred at room temperature for 4 hours. Thecatalyst was removed by filtration and the solvent was concentrated toabout 1 ml under a reduced pressure. This was adjusted to a pH value ofabout 7.5 by adding saturated sodium bicarbonate, and the thusprecipitated crystals were collected by filtration. Thereafter, the thuscollected crystals were dried under a reduced pressure to obtain thetitle compound (10 mg) in white color. ¹H-NMR (CD₃0D) 8 values: 2.30(3H, s), 2.54 (4H, t), 2.73 (3H, s), 3.59 (4H, t), 7.22 (2H, s)

[0149] MS (EI): m/z 294 (M⁺)

INVENTIVE EXAMPLE 12

[0150] 2-(4-Pyridyl)benzoxazole

[0151] A 500 mg portion of pyridine-4-aldehyde was dissolved in 15 ml ofacetic acid, and the solution was mixed with 509 mg of o-aminophenol andstirred with heating at 100° C. for 6 hours. The solvent wasconcentrated under a reduced pressure, and the residual oily matter wasmixed with saturated sodium bicarbonate aqueous solution and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried with magnesium sulfate, and then the solvent was evaporatedunder a reduced pressure. Thereafter, the thus obtained mixture waspurified by a silica gel column chromatography (ethyl acetate:hexane1:1) to obtain the title compound (90 mg) in light yellow color.

[0152]¹H-NMR (CD₃OD) δ values: 7.4-7.5 (2H, m), 7.64 (1H, d), 7.83 (1H,d), 8.10 (2H, d), 8.81 (2H, d)

[0153] MS (EI): m/z 180 (M⁺)

INVENTIVE EXAMPLE 13

[0154] 5,7-Dimethyl-2-(1-piperazinvl)benzoxazole

[0155] A 50 mg-portion of 5,7-dimethyl-2-mercaptobenzoxazole wasdissolved in 5 ml of nitromethane, and the solution was mixed with 240mg of piperazine and heated under reflux for 12 hours. The solvent wasconcentrated under a reduced pressure, and the residual oily matter wasmixed with saturated sodium bicarbonate aqueous solution and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried with magnesium sulfate, and then the solvent was evaporatedunder a reduced pressure. Thereafter, the thus obtained mixture waspurified by a silica gel column chromatography(chloroform:methanol=20:1) to obtain the title compound (35 mg) in whitecolor.

[0156]¹H-NMR (CD₃OD) 8 values: 2.24 (3H, s), 2.28 (3H, s), 2.86 (4H. t),3.54 (4H, t), 6.59 (1H, s), 6.82 (1H, s)

[0157] MS (EI): m/z 231 (M⁺)

INVENTIVE EXAMPLE 14

[0158] 2-(1-Piperazinyl)benzoxazole

[0159] Anhydrous piperazine (5.6 g) was dissolved in methylene chloride(100 ml) to which was subsequently added triethylamine (4.5 ml). Withcooling in an ice bath, to this was added dropwise 2-chlorobenzoxazole(3.7 ml) in small portions, followed by 45 minutes of stirring. Thereaction solution was mixed with water, extracted with methylenechloride and then washed with saturated sodium bicarbonate aqueoussolution and saturated brine in that order. The organic layer was driedwith magnesium sulfate and the solvent was evaporated under a reducedpressure. Thereafter, the thus obtained mixture was purified by a silicagel column chromatography (methanol) to obtain the title compound2-(1-piperazinyl)benzoxazole,(4.751 g) in the form of yellow crystallinepowder.

[0160]¹H-NMR (CDCl₃): δ 2.99 (4H, t), 3.48 (1H, s), 3.68 (4H, t), 7.02(1H, dt), 7.16 (1H, dt), 7.25 (1H, dd), 7.36 (1H, dd)

[0161] EIMS: m/z 204 (M⁺)

INVENTIVE EXAMPLE 15

[0162] 2-(4-Piperidyl)benzoxazole

[0163] 2-Aminophenol (200 mg) and 4-piperidinecarboxylic acid (236 mg)were mixed with polyphosphoric acid (1 g) and stirred with heating at180° C. for 2 hours. After cooling to room temperature, the reaction wasstopped by adding water. The filtrate was adjusted to pH 12 with 50%potassium hydroxide aqueous solution and then extracted with methylenechloride. The organic layer was washed with saturated brine and driedwith magnesium sulfate, and then the solvent was evaporated under areduced pressure to obtain the title compound 2-(4-piperidyl)benzoxazole(311.5 mg).

[0164] 1H-NMR (CDCl₃): δ 1.89 (2H, ddd), 2.16 (2H, dd), 2.79 (2H, dt),3.20 (1H, t), 3.23 (1H, t), 3.05-3.15 (1H, m), 7.27-7.32 (2H, m),7.46-7.52 (1H, m), 7.66-7.72 (1H, m)

[0165] EIMS: m/z 202 (M⁺)

INVENTIVE EXAMPLE 16

[0166] 2-(4-Piperidyl)-5-methylbenzoxazole

[0167] 2-Amino-4-methylphenol (400 mg) and 4-piperidinecarboxylic acid(420 mg) were mixed with polyphosphoric acid (2 g) and stirred withheating at 180° C. for 2 hours. After cooling to room temperature, thereaction was stopped by adding water. The filtrate was adjusted to pH 12with 50% potassium hydroxide aqueous solution and then extracted withmethylene chloride. The organic layer was washed with saturated brineand dried with magnesium sulfate, and then the solvent was evaporatedunder a reduced pressure to obtain the title compound2-(4-piperidyl)-5-methylbenzoxazole (586 mg).

[0168]¹H-NMR (CDCl₃): δ 1.87 (4H, t), 2.14 (1H, d), 2.46 (3H, s), 2.79(2H, t), 3.04-3.14 (1H, m), 3.21 (2H, d), 7.10 (1H, d), 7.35 (1H, d),7.47 (1H, s)

[0169] EIMS: m/z 216 (M⁺)

INVENTIVE EXAMPLE 17

[0170] 2-(4-Methyl-1-piperazinyl)-5-methylbenzoxazole

[0171] Phosphorus pentachloride (227 mg) was dissolved in anhydroustoluene (3 ml), the resulting solution was mixed with2-mercapto-5-methylbenzoxazole (150 mg) which has been obtained in thesame manner as described in Reference Example 1, and the mixture wasthen stirred with heating at 100° C. for 2 hours. With cooling in an icebath, to this was added dropwise N-methylpiperazine (1 ml). After 20minutes of stirring, the thus obtained mixture was extracted with ethylacetate, and the organic layer was washed with saturated sodiumbicarbonate aqueous solution and saturated brine in that order. Afterdrying with magnesium sulfate, the solvent was evaporated under areduced pressure, and the resulting residue was purified by a silica gelcolumn chromatography (methylene chloride:methanol=10:1) to obtain thetitle compound 2-(4-methyl-1-piperazinyl)-5-methylbenzoxazole (188 mg).

[0172]¹H-NMR (CDCl₃): δ 2.35 (3H, s), 2.39 (3H, s), 2.52 (4H, t), 3.71(4H, t), 6.82 (1H, dd), 7.11 (1H, d), 7.15 (1H,

[0173] EIMS: m/z 231 (M⁺)

INVENTIVE EXAMPLE 18

[0174] 2-(4-Methyl-1-piperazinvl)-6-methylbenzoxazole

[0175] Phosphorus pentachloride (302 mg) was dissolved in anhydroustoluene (4 ml), the resulting solution was mixed with2-mercapto-6-methylbenzoxazole (200 mg) which has been obtained in thesame manner as described in Reference Example 1, and the mixture wasthen stirred with heating at 100° C. for 2 hours. With cooling in an icebath, to this was added dropwise N-methylpiperazine (1.34 ml). After 20minutes of stirring, the thus obtained mixture was extracted with ethylacetate, and the organic layer was washed with saturated sodiumbicarbonate aqueous solution and saturated brine in that order. Afterdrying with magnesium sulfate, the solvent was evaporated under areduced pressure, and the resulting residue was purified by a silica gelcolumn chromatography (methylene chloride:methanol=10:1) to obtain thetitle compound 2-(4-methyl-1-piperazinyl)-6-methylbenzoxazole (166 mg).

[0176]¹H-NMR (CDCl₃): δ 2.35 (3H, s), 2.40 (3H, s), 2.52 (4H, t), 3.70(4H, t), 6.97 (1H, d), 7.07 (1H, s), 7.23 (1H, d)

[0177] EIMS: m/z 231 M⁺)

INVENTIVE EXAMPLE 19

[0178] 2-(4-Methyl-1-piperazinvl)-7-methylbenzoxazole Phosphoruspentachloride (454 mg) was dissolved in anhydrous toluene (6 ml), theresulting solution was mixed with 2-mercapto-7-methylbenzoxazole (300mg) which has been obtained in the same manner as described in ReferenceExample 1, and the mixture was then stirred with heating at 100° C. for2 hours. With cooling in an ice bath, to this was added dropwiseN-methylpiperazine (2.0 ml). After 20 minutes of stirring, the thusobtained mixture was extracted with ethyl acetate, and the organic layerwas washed with saturated sodium bicarbonate aqueous solution andsaturated brine in that order. After drying with magnesium sulfate, thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by a silica gel column chromatography (methylenechloride:methanol=10:1) to obtain the title compound2-(4-methyl-1-piperazinyl)-7-methylbenzoxazole (392 mg).

[0179]¹H-NMR (CDCl₃): δ 2.36 (3H, s), 2.42 (3H, s), 2.53 (4H, t), 3.73(4H, t), 6.83 (1H; d), 7.06 (1H, t), 7.19 (1H, d)

[0180] EIMS: m/z 231 (M⁺)

INVENTIVE EXAMPLE 20

[0181] 2-(4-Methyl-1-piperazinyl)-5,7-dichlorobenzoxazole Phosphoruspentachloride (454 mg) was dissolved in anhydrous toluene (6 ml), theresulting solution was mixed with 2-mercapto-5,7-dichlorobenzoxazole(400 mg) which has been obtained in the same manner as described inReference Example 1, and the mixture was then stirred with heating at100° C. for 2 hours. With cooling in an ice bath, to this was addeddropwise N-methylpiperazine (2.0 ml). After 20 minutes of stirring, thethus obtained mixture was extracted with ethyl acetate, and the organiclayer was washed with saturated sodium bicarbonate aqueous solution andsaturated brine in that order. After drying with magnesium sulfate, thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by a silica gel column chromatography (methylenechloride:methanol=10:1) to obtain the title compound2-(4-methyl-1-piperazinyl)-5,7-dichlorobenzoxazole (89.9 mg).

[0182]¹H-NMR (CDCl₃): δ 2.36 (3H, s), 2.53 (4H, t), 3.75 (4H, t), 7.00(1H, d), 7.18 (1H, d)

[0183] EIMS: m/z 285 (M⁺), 287 (M⁺+2), 289 (M⁺+4)

INVENTIVE EXAMPLE 21

[0184] 2-(4-Methyl-1-perazinyl)naphtho[1,2-d]oxazole

[0185] Phosphorus pentachloride (498 mg) was dissolved in anhydroustoluene (8 ml), the resulting solution was mixed with2-mercaptonaphtho[1,2-d]oxazole (400 mg) which has been obtained in thesame manner as described in Reference Example 1, and the mixture wasthen stirred with heating at 100° C. for 2 hours. With cooling in an icebath, to this was added dropwise N-methylpiperazine (2.2 ml). After 20minutes of stirring, the thus obtained mixture was extracted with ethylacetate, and the organic layer was washed with saturated sodiumbicarbonate aqueous solution and saturated brine in that order. Afterdrying with magnesium sulfate, the solvent was evaporated under areduced pressure, and the resulting residue was purified by a silica gelcolumn chromatography (methylene chloride:methanol=10:1) to obtain thetitle compound 2-(4-methyl-1-piperazinyl)naphtho[1,2-d]oxazole (94.9mg).

[0186]¹H-NMR (CDCl₃): δ 2.38 (3H, s), 2:57 (4H, t), 3.80 (4H, t), 7.44(1H, t), 7.47-7.55 (3H, m), 7.88 (1H, d), 8.32 (1H, d)

[0187] EIMS: m/z 267 (M⁺)

INVENTIVE EXAMPLE 22

[0188] 2-(4-Methyl-1-piperazinyl)-5-aminobenzoxazole

[0189] a) Phosphorus pentachloride (1.37 g) was dissolved in anhydroustoluene (18 ml), the resulting solution was mixed with2-mercapto-5-nitrobenzoxazole (900 mg) which has been obtained in thesame manner as described in Reference Example 1, and the mixture wasthen stirred with heating at 100° C. for 3 hours. With cooling in an icebath, to this was added dropwise N-methylpiperazine (6.09 ml). After 20minutes of stirring, the thus obtained mixture was extracted with ethylacetate, and the organic layer was washed with saturated sodiumbicarbonate aqueous solution and saturated brine in that order. Afterdrying with magnesium sulfate, the solvent was evaporated under areduced pressure, and the resulting residue was purified by a silica gelcolumn chromatography (methylene chloride:methanol=10:1) to obtain2-(4-methyl-1-piperazinyl)-5-nitrobenzoxazole (56.1 mg) in the form ofyellow crystalline powder.

[0190]¹H-NMR (CDCl₃): δ 2.37 (3H, s), 2.56 4H, t), 3.71 (4H, t), 7.68(1H, d), 7.96 (1H, d), 8.34 (1H, s)

[0191] EIMS: m/z 262 (M⁺)

[0192] b) 2-(4-Methyl-1-piperazinyl)-5-nitrobenzoxazole (26 mg) obtainedin the above step (a) was dissolved in acetic acid (2 ml), and thesolution was mixed with 10% palladium-carbon (10 mg) and stirredovernight at room temperature in an atmosphere of hydrogen. Thereafter,the reaction solution was filtered through celite, and then the solventwas evaporated under a reduced pressure to obtain the title compound2-(4-methyl-1-piperazinyl)-5-aminobenzoxazole (6.3 mg).

[0193]¹H-NMR (CDCl₃): δ 2.36 (3H, s), 2.56 (4H, t), 3.64 (4H, t), 6.49(1H, dd), 6.91 (1H, d), 7.33 (1H, d)

[0194] EIMS: m/z 233 (M⁺+1)

INVENTIVE EXAMPLE 23

[0195] 2-(4-Methyl-1-piperazinyl)-6-aminobenzoxazole

[0196] a) Phosphorus pentachloride (764 mg) was dissolved in anhydroustoluene (9 ml), the resulting solution was mixed with²-mercapto-6-nitrobenzoxazole (600 mg) which has been obtained in thesame manner as described in Reference Example 1, and the mixture wasthen stirred with heating at 100° C. for 3 hours. With cooling in an icebath, to this was added dropwise N-methylpiperazine (3.4 ml). After 20minutes of stirring, the thus obtained mixture was extracted with ethylacetate, and the organic layer was washed with saturated sodiumbicarbonate aqueous solution and saturated brine in that order. Afterdrying with magnesium sulfate, the solvent was evaporated under areduced pressure, and the resulting residue was purified by a silica gelcolumn chromatography (methylene chloride:methanol=20:1) to obtain2-(4-methyl-1-piperazinyl)-6-nitrobenzoxazole (668.9 mg) in the form ofyellow crystalline powder.

[0197]¹H-NMR (CDCl₃): δ 2.37 (3H, s), 2.56 (4H, t), 3.81 (4H, t), 7.32(1H, d), 8.14 (1H, d), 8.19 (1H, dd)

[0198] EIMS: m/z 262 (M⁺)

[0199] b) 2-(4-Methyl-1-piperazinyl)-6-nitrobenzoxazole obtained in theabove step (a) was dissolved in acetic acid (2 ml), and the solution wasmixed with 10% palladium-carbon (10 mg) and stirred overnight at roomtemperature in an atmosphere of hydrogen. Thereafter, the reactionsolution was filtered through celite and then the solvent was evaporatedunder a reduced pressure to obtain the title compound2-(4-methyl-1-piperazinyl)-6-aminobenzoxazole (35 mg).

[0200]¹H-NMR (CDCl₃): δ 2.36 (3H, s), 2.57 (4H, t), 3.69 (4H, t), 4.30(1H, brs), 6.55 (1H, dt), 6.67 (1H, t), 7.15 (1H, dd)

[0201] EIMS: m/z 233 (M⁺+1)

INVENTIVE EXAMPLE 24

[0202] 2-(4-Methyl-1-piperazinyl)-5-trifluoromethylbenzoxazole

[0203] 2-Mercapto-5-trifluoromethylbenzoxazole (200 mg) which has beenobtained in the same manner as described in Reference Example 1 wasdissolved in chloroform (10 ml), and the solution was mixed withN-methylpiperazine (0.5 ml) and heated overnight under reflux. Thesolvent was evaporated under a reduced pressure, the resulting residuewas mixed with water and then the thus precipitated solid matter wascollected by filtration to obtain the title compound2-(4-methyl-1-piperazinyl)-5-trifluoromethylbenzoxazole (134 mg).

[0204]¹H-NMR (CDCl₃): δ 2.36 (3H, s), 2.54 (4H, t), 3.75 (4H, t), 7.30(2H, d), 7.57 (1H, s)

[0205] LCMS: m/z 286 (M⁺+1)

INVENTIVE EXAMPLE 25

[0206] 1-Allyl-1-methyl-4-(5-methylbenzoxazol-2-yl)piperazinium bromide

[0207] 2-(4-Methyl-1-piperazinyl)-5-methylbenzoxazole (21 mg) obtainedin Inventive Example 17 was dissolved in N,N-dimethylformamide (1 ml),and the solution was mixed with allyl bromide (0.15 ml) and stirredovernight at room temperature. The solvent was evaporated under areduced pressure, the resulting residue was mixed with ethyl acetate andthen the thus precipitated solid matter was collected by filtration toobtain the title compound1-allyl-1-methyl-4-(5-methylbenzoxazol-2-yl)piperazinium bromide (28mg).

[0208]¹H-NMR (CD₃OD): δ 2.43 (3H, s), 3.28 (3H, s), 3.60-3.80 (4H, m),3.98-4.10 (2H, m), 4.14-4.30 (4H, m), 5.80-5.90 (2H, m), 6.12-6.25 (1H,m), 6.99 (1H, d), 7.21 (1H, s), 7.30 (1H, d)

[0209] LCMS: m/z 272 (M⁺)

INVENTIVE EXAMPLE 26

[0210] 1-Allyl-1-methyl-4-(5-trifluoromethylbenzoxazol-2-yl)piperaziniumbromide 2-(4-Methyl-1-piperazinyl)-5-trifluoromethylbenzoxazole (29 mg)obtained in Inventive Example 25 was dissolved in N,N-dimethylformamide(1 ml), and the solution was mixed with allyl bromide (85 μl) andstirred overnight at room temperature. The solvent was evaporated undera reduced pressure, the resulting residue was mixed with ethyl acetateand then the thus precipitated solid matter was collected by filtrationto obtain the title compound1-allyl-1-methyl-4-(5-trifluoromethylbenzoxazol-2-yl)piperaziniumbromide (30 mg).

[0211]¹H-NMR (CD₃OD): δ 3.29 (3H, s), 3.65-3.80 (4H, m), 4.05-4.15 (2H,m), 4.22-4.30 (4H, m), 5.80-5.90 (2H, m), 6.10-6.30 (1H, m), 7.49 (1H,d), 7.61 (1H, d), 7.65 (1H, s)

[0212] LCMS: m/z 326 (M⁺)

INVENTIVE EXAMPLE 27

[0213] 1-Allyl-1-methyl-4-(6-methylbenzoxazol-2-vl)piperazinium bromide

[0214] 2-(4-Methyl-1-piperazinyl)-6-methylbenzoxazole (15 mg) obtainedin Inventive Example 18 was dissolved in N,N-dimethylformamide (0.5 ml),and the solution was mixed with allyl bromide (51 μl) and stirredovernight at room temperature. The solvent was evaporated under areduced pressure, the resulting residue was mixed with ethyl acetate andthen the thus precipitated solid matter was collected by filtration toobtain the title compound1-allyl-1-methyl-4-(6-methylbenzoxazol-2-yl)piperazinium bromide (15mg).

[0215]¹H-NMR (CD₃OD): δ 2.45 (3H, s), 3.27 (3H, s), 3.60-3.80 (4H, m),3.95-4.10 (2H, m), 4.10-4.30 (4H, m), 5.80-5.90 (2H, m), 6.10-6.25 (1H,m), 7.10 (1H, d), 7.26 (1H, s), 7.27 (1H, d)

[0216] LCMS: m/z 272 (M⁺)

INVENTIVE EXAMPLE 28

[0217] 1-Allyl-1-methyl-4-(7-methylbenzoxazol-2-vl)piperazinium bromide

[0218] 2-(4-Methyl-1-piperazinyl)-7-methylbenzoxazole (23 mg) obtainedin Inventive Example 19 was dissolved in N,N-dimethylformamide (1 ml),and the solution was mixed with allyl bromide (85 μl) and stirredovernight at room temperature. The solvent was evaporated under areduced pressure, the resulting residue was mixed with ethyl acetate andthen the thus precipitated solid matter was collected by filtration toobtain the title compound1-allyl-1-methyl-4-(7-methylbenzoxazol-2-yl)piperazinium bromide (34mg).

[0219]¹H-NMR (CD₃OD): δ 2.49 (3H, s), 3.28 (3H, s), 3.60-3.80 (4H, m),4.00-4.15 (2H, m), 4.15-4.30 (4H, t), 5.80-6.00 (2 H, m), 6.10-6.30 (1H,m), 6.99 (1H, d), 7.16 (1H, t), 7.20 (1H, d)

[0220] FABMS: m/z 272 (M⁺)

INVENTIVE EXAMPLE 29

[0221] 1-Allyl-1-methyl-4-(5,7-dichlorobenzoxazol-2-vl)piperaziniumbromide

[0222] 2-(4-Methyl-1-piperazinyl)-5,7-dichlorobenzoxazole (20 mg)obtained in Inventive Example 20 was dissolved in N,N-dimethylformamide(1 ml), and the solution was mixed with allyl bromide (59 μl) andstirred overnight at room temperature. The solvent was evaporated undera reduced pressure, the resulting residue was mixed with ethyl acetateand then the thus precipitated solid matter was collected by filtrationto obtain the title compound1-allyl-1-methyl-4-(5,7-dichlorobenzoxazol-2-yl)piperazinium bromide (27mg).

[0223]¹H-NMR (CD₃OD): δ 3.28 (3H, 9), 3.65-3.77 (4H, m), 4.05-4.15 (2H,m), 4.20-4.30 (4H, m), 5.80-5.90 (2H, m), 6.12-6.25 (1H, m), 7.23 (1H,d), 7.33 (1H, d)

[0224] LCMS: m/z 326 (M⁺)

INVENTIVE EXAMPLE 30

[0225] 1-Allyl-1-methyl-4-(naphtho[1,2-d]benzoxazol-2-yl)piperaziniumbromide

[0226] 2-(4-Methyl-1-piperazinyl)naphtho[1,2-d]oxazole (27 mg) obtainedin Inventive Example 21 was dissolved in N,N-dimethylformamide (1 ml),and the solution was mixed with allyl bromide (85 μl) and stirredovernight at room temperature. The solvent was evaporated under areduced pressure, the resulting residue was mixed with ethyl acetate andthen the thus precipitated solid matter was collected by filtration toobtain the title compound1-allyl-1-methyl-4-(naphtho[1,2-d]benzoxazol-2-yl)piperazinium bromide(33 mg).

[0227]¹H-NMR (CD₃OD): δ 3.30 (3H, s), 3.75-3.80 (4H, m), 4.18-4.20 (2H,m), 4.20-4.32 (4H, m), 5.80-5.90 (2H, m), 6.15-6.30 (1H, m), 7.52 (1H,dt), 7.61 (1H, dt), 7.66 (1H, d), 7.71 (1H, d), 7.99 (1H, d), 8.32 (1H,d)

[0228] FABMS: m/z 308 (M⁺)

INVENTIVE EXAMPLE 31

[0229] 5-Chloro-7-methyl-2-(4-methyl-1-piperazinyl benzoxazole

[0230] 5-Chloro-7-methyl-2-mercaptobenzoxazole (200 mg) was dissolved inchloroform (20 ml), N-methylpiperazine (0.55 ml) was added dropwise tothe solution and then the mixture was stirred with heating for 3 days.After evaporation of the solvent, the thus obtained mixture was purifiedby a silica gel column chromatography (methylene chloride:methanol=20:1)to obtain the title compound5-chloro-7-methyl-2-(4-methyl-1-piperazinyl)benzoxazole (270 mg).

[0231]¹H-NMR (CDCl₃): δ 2.36 (3H, s), 2.37 (3H, s)t 2.53 (4H, t), 3.72(4H, t), 6.81 (1H, d), 7.14 (1H, d)

[0232] SIMS: m/z 266 (M⁺+1), 268 (M⁺+3)

INVENTIVE EXAMPLE 32

[0233] 5-Chloro-2-(1-piperidyl)benzoxazole 2-Amino-4-chlorophenol (400mg) and 4-piperidinecarboxylic acid (360 mg) were mixed withpolyphosphate (2 g) in xylene (30 ml) and stirred with heating at 180°C. for 2 hours. After cooling to room temperature, the reaction wasstopped by adding water. The filtrate was adjusted to pH 12 with 50%potassium hydroxide aqueous solution and extracted with methylenechloride. The organic layer was washed with saturated brine and driedwith magnesium sulfate, and then the solvent was evaporated under areduced pressure to obtain the title compound5-chloro-2-(1-piperidyl)benzoxazole (218 mg).

[0234]¹H-NMR (CDCl₃): δ 1.60-1.75 (2H, m), 1.99 (2H, d), 2.61 (2H, t),2.99 (2 H, d), 3.00-3.20 (1H, m), 4.02 (1H, brs), 7.39 (1H, dd), 7.72(1H, d), 7.81 (1H, d)

[0235] EIMS: m/z 236 (M⁺), 238 (M⁺+2)

INVENTIVE EXAMPLE 33

[0236] 5-Chloro-6,7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole

[0237] 5-Chloro-6,7-dimethyl-2-mercaptobenzoxazole (200 mg) wasdissolved in chloroform (20 ml), N-methylpiperazine (1.54 ml) was addeddropwise to the solution and then the mixture was stirred with heatingfor 29 hours. After evaporation of the solvent, the thus obtainedmixture was purified by a silica gel column chromatography (methylenechloride:methanol=20:1) to obtain the title compound5-chloro-6,7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole (260 mg).

[0238]¹H-NMR (CDCl₃): δ 2.33 (3H, s), 2.35 (3H, s), 2.36 (3H, s), 2.54(4H, t), 3.72 (4H, t), 7.20 (1H, s)

[0239] SIMS: m/z 280 (M⁺+1), 282 (M⁺+3)

INVENTIVE EXAMPLE 34

[0240] 5,7-Dichloro-6-methyl-2-(4-methyl-1-piperazinyl)benzoxazole

[0241] 5,7-Dichloro-6-methyl-2-mercaptobenzoxazole (200 mg) wasdissolved in chloroform (20 ml), N-methylpiperazine (0.94 ml) was addeddropwise to the solution and then the mixture was stirred with heatingfor 29 hours. After evaporation of the solvent, the thus obtainedmixture was purified by a silica gel column chromatography (methylenechloride:methanol=20:1) to obtain the title compound5,7-dichloro-6-methyl-2-(4-methyl-1-piperazinyl)benzoxazole (163 mg).

[0242]¹H-NMR (CDCl₃): δ 2.36 (3H, s), 2.47 (3H, s), 2.53 (4H, t), 3.74(4H, t), 7.26 (1H, s)

[0243] EIMS: m/z 299 (M⁺−1)

INVENTIVE EXAMPLE 35

[0244] 5-Methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole

[0245] 5-Methyl-2-mercaptobenzoxazole (200 mg) was dissolved inchloroform (20 ml), N-methylhomopiperazine (1.24 ml) was added dropwiseto the solution and then the mixture was stirred with heating for 2days. After evaporation of the solvent, the thus obtained mixture waspurified by a silica gel column chromatography (methylenechloride:methanol=10:1) to obtain the title compound5-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (124 mg).

[0246]¹H-NMR (CDCl₃): δ 2.00-2.10 (2H, m), 2.64 (2H, t), 2.76 (2H, t),3.80 (2H, t), 3.86 (2H, t), 6.79 (1H, d), 7.11(1H, d), 7.14 (1H, s)

[0247] SIMS: m/z 246 (M⁺+1)

INVENTIVE EXAMPLE 36

[0248] 5,7-Dimethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole

[0249] 5,7-Dimethyl-2-mercaptobenzoxazole (220 mg) was dissolved inchloroform (20 ml), N-methylhomopiperazine (0.76 ml) was added dropwiseto the solution and then the mixture was stirred with heating for 2days. After evaporation of the solvent, the thus obtained mixture waspurified by a silica gel column chromatography (methylenechloride:methanol=20:1) to obtain the title compound5,7-dimethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (110 mg).

[0250]¹H-NMR (CDCl₃): δ 2.00-2.10 (2H, m), 2.34 (3H, s), 2.36 (3H, s),2.39 (3H, s), 2.60-2.65 (2H, m), 3.76-3.87 (4H, m), 6.62 (1H, s), 6.98(1H, s)

[0251] SIMS: m/z 260 (M⁺+1)

INVENTIVE EXAMPLE 37

[0252] 5-Chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole

[0253] 5-Chloro-7-methyl-2-mercaptobenzoxazole (200 mg) was dissolved intoluene (10 ml), N-methylhomopiperazine (1.24 ml) was added dropwise tothe solution and then the mixture was stirred with heating for 1 hour.After evaporation of the solvent, the thus obtained mixture was purifiedby a silica gel column chromatography (methylene chloride:methanol=10:1)to obtain the title compound5-chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (266 mg).

[0254]¹H-NMR (CDCl₃): δ 2.00-2.07 (2H, m), 2.37 (3H, s), 2.40 (3H, s),2.63 (2H, t), 2.74 (2H, t), 3.79 (2H, t), 3.85 (2H, t), 6.78 (1H, d),7.13 (1H, d)

[0255] SIMS: m/z 280 (M⁺+1), 282 (M⁺+3)

INVENTIVE EXAMPLE 38

[0256] 5-Chloro-7-ethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole

[0257] 5-Chloro-7-ethyl-2-mercaptobenzoxazole (200 mg) was dissolved intoluene (10 ml), N-methylhomopiperazine (1.17 ml) was added dropwise tothe solution and then the mixture was stirred with heating for 5 hours.After evaporation of the solvent, the thus obtained mixture was purifiedby a silica gel column chromatography (methylene chloride:methanol=10:1)to obtain the title compound5-chloro-7-ethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (211 mg).

[0258]¹H-NMR (CDC₃): δ 1.29 (3H, t), 2.00-2.10 (2H, m), 2.41 (3H, s),2.62-2.66 (2H, m), 2.72-2.80 (4 H, m), 3.79 (2H, t), 3.83-3.88 (2H, m),6.80 (1H, d), 7.14 (1H, d)

[0259] SIMS: m/z 294 (M⁺+1), 296 (M⁺+3)

INVENTIVE EXAMPLE 39

[0260] 5-Chloro-6-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole

[0261] 5-Chloro-6-methyl-2-mercaptobenzoxazole (200 mg) was dissolved inchloroform (20 ml), N-methylhomopiperazine (1.24 ml) was added dropwiseto the solution and then the mixture was stirred with heating for 2days. After evaporation of the solvent, the thus obtained mixture waspurified by a silica gel column chromatography (methylenechloride:methanol=20:1) to obtain the title compound5-chloro-6-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (183 mg).

[0262]¹H-NMR (CDCl₃): δ 2.00-2.07 (2H, m), 2.37 (3H, s), 2.40 (3H, s),2.63 (2H, t), 2.74 (2H, t), 3.79 (2H, t), 3.85 (2H, t), 6.78 (1H, d),7.13 (1H, d)

[0263] FABMS: m/z 280 (M⁺+1), 282 (M⁺+3)

INVENTIVE EXAMPLE 40

[0264] 2-(4-Methyl-1-homopiperazinyl)naphtho[1,2-d]oxazole

[0265] 2-Mercapto-naphtho[1,2-d]oxazole (200 mg) was dissolved inchloroform (20 ml), N-methylhomopiperazine (2.48 ml) was added dropwiseto the solution and then the mixture was stirred with heating for 2days. After evaporation of the solvent, the thus obtained mixture waspurified by a silica gel column chromatography (methylenechloride:methanol =10:1) to obtain the title compound2-(4-methyl-1-homopiperazinyl)naphtho[1,2-d]oxazole (137 mg).

[0266]¹H-NMR (CDCl₃): δ 2.04-2.12 (2H, m), 2.41 (3H, s), 2.65 (2H, t),2.79 (2H, t), 3.94 (2H, t), 3.89 (2H, t), 7.43 (1H, t), 7.50 (2H, s),7.52 (1H, t), 7.88 (1H, d), 8.33 (1H, d)

[0267] EIMS: m/z 281 (M⁺)

INVENTIVE EXAMPLE 41

[0268] 5-Chloro-2-(4-methyl-1-homopiperazinyl)benzoxazole

[0269] 5-Chloro-2-mercaptobenzoxazole (1 g) was dissolved in toluene (50ml), N-methylhomopiperazine (3.3 ml) was added dropwise to the solutionand then the mixture was stirred with heating for 2 hours. Afterevaporation of the solvent, the thus obtained mixture was purified by asilica gel column chromatography (methylene chloride:methanol 20:1) toobtain the title compound5-chloro-2-(4-methyl-1-homopiperazinyl)-benzoxazole (882 mg).

[0270]¹H-NMR (CDCl₃): δ 2.03-2.10 (2H, m), 2.42 (3H, s), 2.65-2.70 (2H,m), 2.76-2.82 (2H, m), 3.75-3.88 (4H, m), 6.94 (1H, d), 7.13 (1H, d),7.30 (1H, s)

[0271] EIMS: m/z 265 (M⁺)

INVENTIVE EXAMPLE 42

[0272] 5-Chloro-6-amino-2-(4-methyl-1-homopiperazinyl)benzoxazole

[0273] a) Using 5-chloro-6-nitro-2-mercaptobenzoxazole, the procedure ofInventive Example 41 was repeated to obtain5-chloro-6-nitro-2-(4-methyl-1-homopiperazinyl)benzoxazole.

[0274] b) A 50 mg portion of5-chloro-6-nitro-2-(4-methyl-1-homopiperazinyl)benzoxazole was dissolvedin 15 ml of methanol, and the resulting solution was mixed with 5 ml of1 N hydrochloric acid aqueous solution and 30 mg of Pd/C catalyst and,after replacing the atmosphere in the reaction container by hydrogengas, stirred at room temperature for 15 hours. The catalyst was removedby filtration and the solvent was concentrated under a reduced pressure.The thus remained oily matter was mixed with 5 ml of 1 N hydrochloricacid and washed with ethyl acetate. This was adjusted to pH 8 by addingsaturated sodium bicarbonate, and the thus precipitated crystals werecollected by filtration to obtain the title compound (16 mg).

[0275]¹H-NMR (CDCl₃): δ 2.02-2.13 (2H, m), 2.42 (3H, s), 2.60-2.70 (2H,m), 2.74-2.84 (2H, m), 3.77-3.95 (4H, m), 6.82 (1H, s), 7.29 (1H, s)

[0276] MS (EI): m/z 280 (M⁺)

INVENTIVE EXAMPLE 43

[0277] 5,7-Dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole

[0278] 5,7-Dimethyl-2-mercapto-benzoxazole (109 mg) was dissolved intoluene (6 ml), and the solution was mixed with 1,4-diazacyclooctane(1.93 g) which has been obtained in accordance with the method describedin Carib. J. Sci., 14, 77 (1974) and then stirred with heating for 3hours. After evaporation of the solvent, the thus obtained mixture waspurified by a silica gel column chromatography (methylenechloride:methanol=5:1) to obtain the title compound5,7-dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole (271 mg).

[0279]¹H-NMR (CDCl₃): δ 1.88 (4H, quin), 2.36 (3H, s), 2.38 (3H, s),3.24 (2H, t), 3.41 (2H, t), 3.88 (2H, t), 4.10 (2H, t), 6.67 (1H, s),7.00 (1H, s)

[0280] SIMS: m/z 260 (M⁺+1)

INVENTIVE EXAMPLE 44

[0281] 5,7-Dimethyl-2-(4-methyl-1,4-diazacyclooctanyl)benzoxazole

[0282] 5,7-Dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole (135 mg) wasdissolved in methanol (3 ml), and the solution was mixed with 37%formaldehyde solution (1 ml) and 1 N hydrochloric acid (0.5 ml). Thiswas further mixed with 10% palladium-carbon (10 mg) and stirredovernight in an atmosphere of hydrogen. After removing the catalyst bycelite filtration, the filtrate was washed with ethyl acetate and thenthe solvent was evaporated. The thus obtained residue was extracted with1 N hydrochloric acid and ethyl acetate, and the resulting water layerwas adjusted to pH 8 with potassium carbonate and extracted withmethylene chloride. The organic layer was dried with magnesium sulfateand the solvent was evaporated to obtain the title compound5,7-dimethyl-2-(4-methyl-1,4-diazacyclooctanyl)benzoxazole (50 mg).

[0283]¹H-NMR (CDCl₃): δ 1.60-1.70 (2H, m), 1.92 (2H, quin), 2.35 (3H,s), 2.37 (3H, s), 2.44 (3H, s), 2.55-2.65 (2H, m), 2.75-2.90 (2H, m),3.70-3.76 (2H, m), 3.82 (2H, t), 6.61 (1H, s), 6.98 (1H, s)

[0284] SIMS: m/z 274 (M⁺+1)

FORMULATION EXAMPLE 1

[0285] Preparation of Tablets

[0286] The compound of Inventive Example 13 (10.0 g) was mixed withlactose (85.5 g), hydroxypropyl cellulose HPC-SL (2.0 g), hydroxypropylcellulose L-HPC, LH-22-(2.0 g) and purified water (9.0 g), the resultingmixture was subjected to granulation, drying and grading, and the thusobtained granules were mixed with magnesium stearate (0.5 g) andsubjected to tablet making, thereby obtaining tablets containing 10 mgper tablet of the compound of Inventive Example 13.

FORMULATION EXAMPLE 2

[0287] Preparation of Fine Subtilaes

[0288] The compound of Inventive Example 13 (10.0 g) was mixed withlactose (960 g), hydroxypropyl cellulose HPC-SL (20.0 g) and purifiedwater (90 g), the resulting mixture was subjected to granulation,drying, grading and screening and then mixed with magnesium stearate(10.0 g), thereby obtaining fine subtilaes containing 10 mg per 1.0 g ofthe compound of Inventive Example 13.

TEST EXAMPLE 1

[0289] Toxicity Test

[0290] The compound of Inventive Example 13 or 28 of the presentinvention was dissolved in water and orally administered tofive-week-old male mice (5 animals). No mortal case was found with thedose of 300 mg/kg of the compound of Inventive Example 13 or 28.

TEST EXAMPLE 2

[0291] 5-HT₃ Receptor Activating Action Test

[0292] Of the novel and known benzoxazole compounds according to thepresent invention, typical compounds and the compounds disclosed inJP-A-6-345744, namely 5-methoxy-2-(4-methyl-1-piperazinyl)benzoxazole(A) and 2-(4-methyl-1-piperazinyl)naphtho[2,3-d]oxazole (B), weremeasured for their serotonin 5-HT₃ receptor antagonism and serotonin5-HT₃ receptor activating action by the following method, with theresults shown in Table 1. Test compounds of the present invention areshown by the Inventive Example numbers.

[0293] Longitudinal muscle samples of about 20 mm were prepared from theileum of Hartley male guinea pigs (500 to 800 g). Each of the thusprepared samples was hung down in a Magnus tube with a resting tensionof about 0.5 g to measure the isometric contraction reaction. Serotonin5-HT was applied with a concentration of from 0.1 to 30 μM to the samplewhich has been subjected twice in advance to 1 hour of treatment with0.3 μM serotonin 5-HT to effect desensitization of serotonin 5-HT₄receptor. When the concentration-dependent contraction reaction mediatedby the serotonin 5-HT₃ receptor was observed in this manner, the maximumreaction was found at 10 μM.

[0294] The i.a. value was expressed as the ratio of the maximum reactionof each compound when the maximum contraction reaction obtained by 10 μMof serotonin 5-HT was defined as 1. The pD₂ value was expressed as thenegative logarithmic value of concentration (molar concentration) bywhich 50% of the maximum contraction reaction of each test compound canbe obtained. Also, antagonism of each test compound against theserotonin 5-HT₃ receptor was calculated as the inhibition ratio of thecontraction obtained by applying 10 μM of serotonin 5-HT (manufacturedby Sigma) to a sample which has been treated with 10 mM of each testsample to the contraction obtained by applying 10 μM of serotonin 5-HTto the sample before treatment. TABLE 1 Antagonism Activation ActionExample No. (10 μM, %) i.a. pD₂ 1 92 0.55 6.40 2 90 0.57 6.65 5 95 0.596.17 7 67 0.94 6.50 10 88 0.69 6.17 13 100 0.18 7.00 14 75 0.59 5.74 1682 0.24 6.21 21 85 0.26 6.30 25 86 0.79 6.15 31 85 0.24 6.70 36 96 0.287.20 37 98 0.15 7.70 39 89 0.21 7.00 40 89 0.21 7.10 A 34 — — B 85 0.455.40

[0295] The compound A is possessed of serotonin 5-HT₃ receptorantagonism but does not have serotonin 5-HT₃ receptor activating action.Also, the compound B has serotonin 5-HT₃ receptor antagonism, but itsserotonin 5-HT₃ receptor activating action is weak in comparison withthe compounds of the present invention. On the contrary, it wasconfirmed that the novel and known benzoxazole derivatives of thepresent invention have excellent serotonin 5-HT₃ receptor partialactivation function having strong serotonin 5-HT₃ receptor activatingaction in addition to the -serotonin 5-HT₃ receptor antagonism.

[0296] The benzoxazole derivatives of the present invention are usefulas serotonin 5-HT₃ receptor partial activators.

[0297] Thus, as has been described in the foregoing, the benzoxazolederivatives of the present invention are possessed of serotonin 5-HT₃receptor partial activation function having both serotonin 5-HT₃receptor antagonizing and activating actions. The benzoxazole compoundsof the present invention are useful as serotonin 5-HT₃ receptor partialactivators not only for the inhibition of emesis caused by the use ofcisplatin and the like carcinostatic agents or by radiation treatmentsand for the prevention and treatment of difficulty of gastrointestinalmoving, irritable colon syndrome and the like, but also for thetreatment of headache, neuralgia, anxiety, depression, psychosis and thelike. They are particularly useful in the prevention and treatment ofdifficulty of gastrointestinal moving and irritable colon syndrome as anantidiarrheal drug which does not cause constipation as a side effect.

[0298] While the invention has been described in detail and withreference to specific embodiments thereof, it will be apparent to oneskilled in the art that various changes and modifications can be madetherein without departing from the spirit and scope thereof.

What is claimed is:
 1. A compound represented by formula (1):

wherein R₁ to R₄ may be the same or different from one another and eachrepresents a hydrogen atom, a halogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group or a substituted or unsubstituted amino group, in whichthe substituent for said lower alkyl or lower alkenyl group is selectedfrom the group consisting of a halogen atom, a hydroxyl group, acarbamoyl group, an amino group and a cyano group, and the substituentfor said amino group is selected from the group consisting of a straightor branched C₁-C₄ alkyl group, a straight or branched C₁-C₄alkylcarbonyl group, a straight or branched C₂-C₄ alkenyl group and abenzylidene group which may have phenyl group, or optional two groups ofR₁ to R₄ may be linked together to form a ring structure which is a 5-or 6-membered ring composed of carbon atoms alone or carbon atoms and 1to 2 hetero atoms, selected from a cyclohexane ring, a benzene ring, apyridine ring, a piperidine ring and a pyrrolidine ring; Y represents asaturated or unsaturated, substituted or unsubstituted 4- to 8-memberedhetero ring containing 1 to 3 nitrogen atoms as the ring constitutingatoms and carbon atoms as the remaining atoms, which is a ring selectedfrom the group consisting of an azetidine ring, a pyrrolidine.ring, apiperidine ring, a pyridine ring, an imidazole ring, a pyrazinyl ring, apyridazinyl ring, a triazole ring, a homopiperidine ring, a1,4-diazacyclooctanyl ring and a 1,5-diazacyclooctanyl ring, in whichthe substituent for Y is a group which is linked to a nitrogen atom of Yand selected from the group consisting of a straight or branched C₁-C₄alkyl group and a straight or branched C₂-C₄ alkenyl groups), said loweralkyl group means a straight or branched C₁-C₄ alkyl group, said loweralkenyl group means a straight or branched C₂-C₄ alkenyl group, and saidhalogen atom is selected from the group consisting of fluorine,chlorine, bromine and iodine atoms.
 2. The compound according to claim 1, wherein said Y in the formula (1) is a 4-pyridinyl group, a4-piperidinyl group, a 4-homopiperidinyl group, a1-(1,4-diazacyclooctanyl) group, a 1-(1,5-diazacyclooctanyl) group or a3-pyrrolidinyl group.
 3. A compound represented by formula (2):

wherein R₁ to R₄ may be the same or different from one another and eachrepresents a hydrogen atom, a halogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group or a substituted or unsubstituted amino group, or twogroups of R₁ and R₂ may be linked together to form a benzene ringstructure, with the proviso that compounds in-which all of R₁ to R₄ arehydrogen atoms are excluded; R₅ represents a hydrogen atom, asubstituted or unsubstituted lower alkyl group or a substituted orunsubstituted lower alkenyl group; and m is an integer of 1 to 4, inwhich said lower alkyl group means a straight or branched C₁-C₄ alkylgroup, said lower alkenyl group means a straight or branched C₂-C₄alkenyl group, the substituent for said lower alkyl or lower alkenylgroup is selected from the group consisting of a halogen atom, ahydroxyl group, a carbamoyl group, an amino group and a cyano group, thesubstituent for said amino group is selected from the group consistingof a straight or branched C₁-C₄ alkyl group, a straight or branchedC₁-C₄ alkylcarbonyl group, a straight or branched C₂-C₄ alkenyl groupand a benzylidene group which may have a phenyl group, and said halogenatom is selected from the group consisting of fluorine, chlorine,bromine and iodine atoms.
 4. The compound according to claim 3 , whereinR₁ to R₄ in the formula (2) may be the same or different from oneanother and each represents a hydrogen atom, a halogen atom or asubstituted or unsubstituted lower alkyl group, or two groups of R₁ andR₂ may be linked together to form a benzene ring; R₅ is a substituted orunsubstituted lower alkyl group; and m is an integer of 2 or
 3. 5. Acompound represented by formula (3):

wherein R₁ to R₄ may be the same or different from one another and eachrepresents a hydrogen atom, a halogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group or a substituted or unsubstituted amino group, or twogroups of R₁ and R₂ may be linked together to form a benzene ringstructure, with the proviso that compounds in which all of R₁ to R₄ arehydrogen atoms are excluded; R₅ and R₆ may be the same or different fromeach other and each represents a substituted or unsubstituted loweralkyl group or a substituted or unsubstituted lower alkenyl group; m isan integer of 1 to 4, in which sid lower alkyl group means a straight orbranched C₁-C₄ alkyl group, said lower alkenyl group means a straight orbranched C₂-C₄ alkenyl group, the substituent for said lower alkyl orlower alkenyl group is selected from the group consisting of a halogenatom, a hydroxyl group, a carbamoyl group, an amino group and a cyanogroup, the substituent for said amino group is selected from the groupconsisting of a straight or branched C₁-C₄ alkyl group, a straight orbranched C₁-C₄ alkylcarbonyl group, a straight or branched C₂-C₄ alkenylgroup and a benzylidene group which may have phenyl group, and saidhalogen atom is selected from the group consisting of fluorine,chlorine, bromine and iodine atoms), and X- represents a halogen ion. 6.A pharmaceutical composition which comprises, as its active ingredient,the compound of any one of claims 1 to 5 or a compound represented byformula (4);

wherein m is an integer of 1 to
 4. 7. The pharmaceutical compositionaccording to claim 6 , wherein it is a serotonin 5-HT₃ receptorantagonist or a serotonin 5-HT₃ receptor partial activator.
 8. Thepharmaceutical composition according to claim 6 , wherein it is a drugfor use in the treatment and prevention of functional disorders ofdigestive organs.
 9. The pharmaceutical composition according to claim 6, wherein it is a drug for use in the treatment and prevention ofdiarrhea.
 10. A method for treating or preventing functional disordersof digestive organs, which comprises the step of administering thepharmaceutical composition of claim 6 as a serotonin 5-HT₃ receptorantagonist or a serotonin 5-HT₃ receptor partial activator to mammalsincluding human.
 11. A method for preventing diarrhea, which comprisesthe step of administering the pharmaceutical composition of claim 6 tomammals including human.